One approach to improving vaccination rates is to enhance the efficacy of vaccines by increasing immunological responses such that the number of dosing days can be reduced. In keeping with the mission of the NIH, it is the goal of this proposal to develop a more efficacious hepatitis B vaccine regimen by combining parenteral and oral delivery platforms and monitoring both systemic and mucosal immunological responses in mice. Until now, a practical oral vaccine with commercial potential has not been available to test a combination oral/parenteral vaccine regimen. Recent improvements in technology have led to a practical expression system for a lead hepatitis B vaccine candidate in a wafer formulation. The system has demonstrated that it can be used to provide a robust long-term immune response in animals when orally delivered and has the production and stability requirements to eliminate the cold chain. The goal of this project is to produce a more efficacious vaccine by inducing high serum and mucosal titers after two dosing days. Serum, fecal, and uro-genital antibody production will be analyzed in mice and correlates of protection using the WHO International Standard will be determined. Successful completion of this project will lead to an improvement in the overall immune response and provide the necessary preliminary data for continued preclinical testing. This will pave the way to develop other vaccines using this vaccination model. The intended outcome is that more efficacious vaccines emerge which will result in greater vaccination rates and a reduction in the prevalence of preventable diseases.